Cyanide poisoning can present in multiple ways, given its widespread industrial use, presence in combustion products, multiple physical forms, and chemical structures. The primary target of toxicity is mitochondrial cytochrome oxidase. The onset and severity of poisoning depend on the route, dose, physicochemical structure and other variables. Common poisoning features include dyspnea, altered respiratory patterns, abnormal vital signs, altered mental status, seizures, and lactic acidosis. Our present knowledge supports cyanide poisoning treatment based on excellent supportive care with adjunctive antidotal therapy. Multiple antidotes exist and vary in regional availability. All currently marketed antidotes appear to be effective. Antidotal mechanisms include chelation, formation of stable, less toxic complexes, methemoglobin induction, and sulfane sulfur supplementation for detoxification by endogenous rhodanese. Each antidote has advantages and disadvantages. For example, hydroxocobalamin is safer than the methemoglobin inducers in patients with smoke inhalation. Research for new, safer and more effective cyanide antidotes continues.